Scientists have found out why muscle stem cells need the TRF2 protein.

After injury, the mice almost did not form new muscle fibers if the TRF2 protein was absent in the stem cells responsible for recovery. Fat and scar tissue accumulated in the area of injury. Scientists from the USA and Canada have found that protein helps cells maintain their ability to repair muscles and replenish their own reserves. About why cells without TRF2 stopped coping with recovery and what it means for the study of Duchenne muscular dystrophy — in the material of Izvestia.

How does a muscle recover from injury

Next to the fibers of skeletal muscles are cells called muscle stem cells, or satellite cells. In healthy tissue, most of them are at rest. Once damaged, they activate and multiply. Some of their descendants are involved in the formation and repair of muscle fibers, and some return to a resting state, preserving a supply of cells for future repair.

Scientists from the Perelman School of Medicine at the University of Pennsylvania and their colleagues studied how cells move from rest to recovery. In the course of their work, they noticed that the level of the TRF2 protein changes at different stages of this process.

TRF2 is primarily known as part of the complex protecting telomeres, the terminal regions of chromosomes. Their protection helps the cell distinguish the normal end of a chromosome from a DNA break. In the new work, scientists have studied what happens if TRF2 disappears from muscle stem cells. This approach allowed us to find out what role the protein plays in the cells responsible for tissue repair.

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Why did scar tissue appear at the site of the injury?

At first, the animals' muscles looked normal on the outside. Over time, there have been fewer cells with the characteristic features of muscle stem cells. The researchers checked whether this could be explained by cell death, and found no signs of it in the tests performed. Tracking the cells showed that they were preserved in the tissue, although the activity of the genes determining their specialization was changing.

After the injury to the muscle, the differences became more noticeable. After two weeks, the muscle structure was restored in the control animals. In mice without TRF2, pronounced fibrosis and accumulation of adipose tissue were observed in stem cells at the site of injury. The muscle mass in the studied area continued to decrease. However, at the beginning of the recovery, the cells were still able to divide. The failure occurred in the following stages, when they needed to participate in the formation of fibers and replenish the reserve.

The scientists separately looked at whether the cells returned to their usual place next to the muscle fiber. After damage, a part of the cells normally occupies this niche and goes back to rest. By the tenth day after injury, animals without TRF2 had fewer cells with characteristic signs of muscle stem cells in the niche. With such a violation, the tissue loses part of the reserve that it could count on for the next damage.

What happens to the DNA of muscle stem cells

The scientists tested whether the disorders are related to the well-known function of TRF2 at the ends of chromosomes. In the studied cells, the telomere length did not differ significantly, and the verified signs of DNA damage in these areas did not increase. Instead, the authors found changes in the activity of genes that help muscle stem cells maintain their condition and perform their work after injury.

One of these genes is Pax7. It is involved in maintaining the properties of muscle stem cells. The scientists found TRF2 next to the DNA region that regulates the activity of this gene. In a number of such sites, there were sequences capable of forming G-quadruplexes. This is the name of the structures that arise when a guanine-rich DNA fragment is folded in a special way. This finding helps to understand where TRF2 can influence gene activity. Exactly how the protein changes their work in each specific case remains to be seen.

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What has the experience with muscular dystrophy shown?

Duchenne muscular dystrophy is associated with changes in the DMD gene. Because of them, the body does not produce enough functional dystrophin. This protein helps protect muscle fibers from damage during contraction. With the disease, the fibers are damaged over and over again, so the tissue's ability to repair itself is especially important.

The authors tested what happens if TRF2 is disrupted in muscle stem cells in mice with a model of this disease. In such animals, muscle damage increased faster. The diaphragm, which is involved in breathing, was particularly affected. None of the 23 mice in this group lived longer than 28 weeks. The result helps explain how impaired recovery can aggravate the course of the disease with an existing dystrophin defect.

The researchers want to find out if it is possible to preserve the ability of muscle cells to recover from dystrophy in the future. To do this, you need to confirm that the described mechanism works in humans, and understand how to selectively influence it. TRF2 is involved in several DNA-related processes, so it will be necessary to check the effects on other cells before possible use.

The authors also want to understand how skeletal muscle retains its ability to repair itself in the relatively rare occurrence of tumors in this tissue. During recovery, the cells must start dividing in time and then proceed to fiber formation or return to a dormant state. By studying this transition, the researchers hope to learn how cells maintain control over growth. For future treatment, it is important to find out whether it will be possible to support muscle recovery without increasing the risk of tumors.